Reversible Generation of Metastable Enols in the 1,4-Addition of Thioacetic Acid to α,β-Unsaturated Carbonyl Compounds

Hintermann, Lukas; Turočkin, Aleksej

doi:10.1021/jo3021709

Cited by 6 publications

(1 citation statement)

References 20 publications

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“…However, chemoselective removal of a non enolic CC double bond removes the aromatic resonance energy and provides a novel entry to a new enol, 2 , with very different properties to the parent phenol. Although several methods for preparing enols have been reported, including hydration of alkynes, hydrolysis of enol ethers, , decarboxylation of β-keto acids, isomerization of allyl alcohols, 1,4-addition of thioacetic acid to enals and photochemical fragmentations, the present enzymatic approach is novel, as it is the first method of asymmetric synthesis for preparing a chiral enol by a dearomatisation of a phenol. There is normally a large thermodynamic driving force for enols to tautomerise, to the corresponding carbonyl compounds, but since the activation energy for intramolecular migration of hydrogen is high, enols can be regarded as being metastable.…”

Section: Resultsmentioning

confidence: 99%

Toluene Dioxygenase-Catalyzed Synthesis and Reactions of cis-Diol Metabolites Derived from 2- and 3-Methoxyphenols

et al. 2015

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Using toluene dioxygenase as biocatalyst, enantiopure cis-dihydrodiol and cis-tetrahydrodiol metabolites, isolated as their ketone tautomers, were obtained from meta and ortho methoxyphenols. Although these isomeric phenol substrates are structurally similar, the major bioproducts from each of these biotransformations were found at different oxidation levels. The relatively stable cyclohexenone cis-diol metabolite from meta methoxyphenol was isolated, while the corresponding metabolite from ortho methoxyphenol was rapidly bioreduced to a cyclohexanone cis-diol. The chemistry of the 3-methoxycyclohexenone cis-diol product was investigated and elimination, aromatization, hydrogenation, regioselective O-exchange, Stork-Danheiser transposition and O-methylation reactions were observed. An offshoot of this technology provided a two-step chemoenzymatic synthesis, from meta methoxyphenol, of a recently reported chiral fungal metabolite; this synthesis also established the previously unassigned absolute configuration.

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Section: Resultsmentioning

confidence: 99%

Toluene Dioxygenase-Catalyzed Synthesis and Reactions of cis-Diol Metabolites Derived from 2- and 3-Methoxyphenols

et al. 2015

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Cu(II)-catalyzed tandem synthesis of 2-imino[1,3]benzothiazines from 2-aminoaryl acrylates via thioamidation and concomitant chemoselective thia-Michael addition

Saunthwal

Patel

Kumar

et al. 2015

Tetrahedron Letters

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Kinetics and Thermodynamics of Reversible Thiol Additions to Mono- and Diactivated Michael Acceptors: Implications for the Design of Drugs That Bind Covalently to Cysteines

Petter²,

2016

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Additions of cysteine thiols to Michael acceptors underpin the mechanism of action of several covalent drugs (e.g., afatinib, osimertinib, ibrutinib, neratinib, and CC-292). Reversible Michael acceptors have been reported in which an additional electron-withdrawing group was added at the α-carbon of a Michael acceptor. We have performed density functional theory calculations to determine why thiol additions to these Michael acceptors are reversible. The α-EWG group stabilizes the anionic transition state and intermediate of the Michael addition, but less intuitively, it destabilizes the neutral adduct. This makes the reverse reaction (elimination) both faster and more thermodynamically favorable. For thiol addition to be reversible, the Michael acceptor must also contain a suitable substituent on the β-carbon, such as an aryl or branched alkyl group. Computations explain how these structural elements contribute to reversibility and the ability to tune the binding affinities and the residence times of covalent inhibitors.

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Reversible Generation of Metastable Enols in the 1,4-Addition of Thioacetic Acid to α,β-Unsaturated Carbonyl Compounds

Cited by 6 publications

References 20 publications

Toluene Dioxygenase-Catalyzed Synthesis and Reactions of cis-Diol Metabolites Derived from 2- and 3-Methoxyphenols

Toluene Dioxygenase-Catalyzed Synthesis and Reactions of cis-Diol Metabolites Derived from 2- and 3-Methoxyphenols

Cu(II)-catalyzed tandem synthesis of 2-imino[1,3]benzothiazines from 2-aminoaryl acrylates via thioamidation and concomitant chemoselective thia-Michael addition

Kinetics and Thermodynamics of Reversible Thiol Additions to Mono- and Diactivated Michael Acceptors: Implications for the Design of Drugs That Bind Covalently to Cysteines

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